Most therapeutic dosage forms include mixtures of one or more active pharmaceutical ingredients (APIs) with additional components referred to as excipients. APIs are substances that exert a pharmacological effect on a living tissue or organism, whether used for prevention, treatment, or cure of a disease. APIs can be naturally occurring or synthetic substances, or can be produced by recombinant methods, or any combination of these approaches.
Numerous methods have been devised for delivering APIs into living organisms, each with more or less success. Traditional oral therapeutic dosage forms include both solids (tablets, capsules, pills, etc.) and liquids (solutions, suspensions, emulsions, etc.). Parenteral dosage forms include solids and liquids as well as aerosols (administered by inhalers, etc.), injectables (administered with syringes, micro-needle arrays, etc.), topicals (foams, ointments, etc.), and suppositories, among other dosage forms. Although these dosage forms might be effective in delivering low molecular weight APIs, each of these various methods suffers from one or more drawbacks, including the lack of bioavailability as well as the inability to completely control either the spatial or the temporal component of the API's distribution when it comes to high molecular weight APIs. These drawbacks are especially challenging for administering biotherapeutics, i.e. pharmaceutically active peptides (e.g. growth factors), proteins (e.g. enzymes, antibodies), oligonucleotides and nucleic acids (e.g. RNA, DNA, PNA, aptamers, spiegelmers), hormones and other natural substances or synthetic substances mimicking such, since many types of pharmacologically active biomolecules at least partially are broken down either in the digestive tract or in the blood system and are delivered suboptimally to the target site.
Therefore, an ongoing need exists for improved drug-delivery methods in the life sciences, including but not limited to human and veterinary medicine. One important goal for any new drug-delivery method is to deliver the desired therapeutic agent(s) to a specific place in the body over a specific and controllable period of time, i.e. controlling the delivery of one or more substances to specific organs and tissues in the body in both a spatial and temporal manner. Methods for accomplishing this spatially and temporally controlled delivery are known as controlled-release drug-delivery methods. Delivering APIs to specific organs and tissues in the body offers several potential advantages, including increased patient compliance, extending activity, lowering the required dose, minimizing side effects, and permitting the use of more potent therapeutics. In some cases, controlled-release drug-delivery methods can even allow the administration of therapeutic agents which would otherwise be too toxic or ineffective for use.
There are five broad types of solid dosage forms for controlled-delivery oral administration: reservoir and matrix diffusive dissolution, osmotic, ion-exchange resins, and prodrugs. For parenterals, most of the above solid dosage forms are available as well as injections (intravenous, intramuscular, etc.), transdermal systems, and implants. Numerous products have been developed for both oral and parenteral administration, including depots, pumps, micro- and nano-particles.
The incorporation of APIs into polymer matrices acting as a core reservoir is one approach for controlling their delivery. Contemporary approaches for formulating such drug-delivery systems are dependent on technological capabilities as well as the specific requirements of the application. For sustained delivery systems there a two main structural approaches: the release controlled by diffusion through a barrier such as shell, coat, or membrane, and the release controlled by the intrinsic local binding strength of the API(s) to the core or to other ingredients in the core reservoir.
Another strategy for controlled delivery of therapeutic agents, especially for delivering biotherapeutics, involves their incorporation into polymeric micro- and nano-particles either by covalent or cleavable linkage or by trapping or adsorption inside porous network structures. Various particle architectures can be obtained, for instance core/shell structures. Typically one or more APIs are contained either in the core, in the shell, or in both components. Their concentration can be different throughout the respective component in order to modify the release pattern. Although polymeric nano-spheres can be effective in the controlled delivery of APIs, they also suffer from several disadvantages. For example, their small size can allow them to diffuse in and out of the target tissue or being successfully attacked by macrophages. The use of intravenous nano-particles may also be limited due to rapid clearance by the reticuloendothelial system. Notwithstanding this, polymeric micro-spheres remain an important delivery vehicle.
In view of the above, there is a need for improving drug-delivery methods and compositions.